Cutaneous T-cell lymphoma (CTCL) is a primary cutaneous non-Hodgkin's lymphoma that includes, in its most common manifestation, mycosis fungoides, a clonal malignancy of epidermotropic CD4+ T-cells. While early-stage CTCL generally has a good prognosis and responds well to initial therapies, disease relapse is common and therapeutic options are often exhausted. Topical BCNU can induce response in CTCL, although its clinical use has been limited by systemic and topical toxicities. Recent investigational efforts have focused on O6-benzylguanine (O6BG), which irreversibly inactivates O6-alkylguanine DNA alkyltransferase (AGT), a DNA repair enzyme encoded by the gene MGMT that is responsible for nitrosourea resistance in many malignancies, including CTCL. By inhibiting the activity of AGT, O6BG promotes BCNU-induced DNA adduct formation, cytotoxicity, and subsequent apoptosis of neoplastic cells. A Phase I clinical trial has evaluated intravenous O6BG plus topical BCNU for the treatment of early-stage CTCL, and has demonstrated significant clinical efficacy with an overall response rate of 80%, and minimal systemic and cutaneous toxicity. This trial has established the most significant response rate seen with the O6BG/BCNU regimen, and has demonstrated that AGT inactivation in lesional skin is prevalent through 24 hours post-infusion, although not all patients achieved total AGT depletion. Based on the Phase I trial observations, the objectives of this proposal are the following: 1) To determine the response rate and safety of O6BG/BCNU when given as two consecutive daily doses every two weeks in the treatment of CTCL, and 2) To determine the laboratory correlates of clinical response and drug efficacy based upon the following surrogate marker studies: AGT activity in CTCL lesions will be examined to determine the effects of consecutive day O6BG administration on the extent and duration of AGT depletion; degree of induction of apoptosis and cell cycle arrest will be examined in the malignant T-cell population of lymphomatous tissue and in the constitutive cells of the skin to determine drug efficacy and toxicity; MGMT gene mutations and changes in AGT expression will be examined as potential mechanisms for O6BG resistance in non-responding patients. The long-term objective of this investigation is to design an O6BG/BCNU regimen that optimizes clinical efficacy and toxicity relative to standard CTCL therapies. [unreadable] [unreadable]